1. Field of the Invention
The present invention relates to the use of RARxcex1 specific or selective retinoid compounds in combination with interferons and other anti-tumor agents. More particularly the present invention relates to the use of RARxcex1 specific or selective retinoid compounds for the treatment of carcinoma of the breast in combination with interferons and other anti-tumor agents. Still more particularly, the present invention relates to the use of 4-[(4-chloro-3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene-2-carbonyl)-amino]-2,6-difluoro-benzoic acid and related compounds in combination with interferons and other anti-tumor agents, and specifically to the use of 4-[(4-chloro-3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene-2-carbonyl)-amino]-2,6-difluoro-benzoic acid and related compounds for the treatment of carcinoma of the breast in combination with interferons and other anti-tumor agents.
2. Background Art
Naturally occurring retinoic acid and related compounds, generally called retinoids, have been known in the biopharmaceutical, medical and related arts to have of important biological activity, including prevention and inhibition of malignant cell proliferation. A vast volume of patent and scientific literature exists describing the synthesis of retinoid compounds, their biological activities and investigations aimed at discovering the varying modes of action of retinoids in human and and other biological systems, in vitro and in vivo as well.
Specifically, it is generally accepted in the art that in the anti-cell-proliferative or anti-tumor field, pharmaceutical compositions having a retinoid-like compound or compounds as the active ingredient are useful for treating or preventing hyperproliferative disorders of the skin, and other premalignant and malignant hyperproliferative diseases such as cancers of the breast, skin, prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung, larynx, oral cavity, blood and lymphatic system, metaplasias, dysplasias, neoplasias, leukoplakias and papillomas of the mucous membranes and in the treatment of Kaposi""s sarcoma. However, a generally recognized disadvantage of treatment of mammals by retinoids is their mucocutaneous toxicity which occurs in greater than 90% of patients when treated with an effective dose of retinoids, topically or systemically.
It is now also general knowledge in the art that two main types of retinoid receptors exist in mammals (and other organisms). The two main types or families of receptors are respectively designated the RARs and RXRs. Within each type there are subtypes; in the RAR family the subtypes are designated RARxcex1, RARxcex2 and RARxcex3, in RXR the subtypes are: RXRxcex1, RXRxcex2 and RXRxcex3. It has also been established in the art that the distribution of the two main retinoid receptor types, and of the several sub-types is not uniform in the various tissues and organs of mammalian organisms. Moreover, it is generally accepted in the art that many unwanted side effects of retinoids, such as the mucocutaneous toxicity are mediated by one or more of the RAR receptor subtypes. A publication by Standeven et al., Toxicology Letters 92 (1997) 231-240 discloses that treatment of mice by RARxcex1 selective retinoids results in significantly reduced skin irritation (mucocutaneous toxicity) than treatment with retinoids which have strong RARxcex2 and particularly RARxcex3 agonist activity.
U.S. Pat. No. 5,965,606 discloses methods of treatment of tumors with RARxcex1 specific or selective retinoids, and the synthesis of such retinoids is described in this patent as well as in U.S. Pat. No. 5,856,490. An important RARxcex1 selective compound of U.S. Pat. No. 5,965,606 (Compound 32 of this patent reference) is shown below.
With regard to using retinoids in combination with other drugs to treat tumors, there are published reports in the art that certain retinoid compounds act additively and some even synergistically with other known anti-tumor chemotherapeutic agents, such as interferons and other drugs, in several carcinoma of the breast cell cultures to suppress or inhibit the proliferation of the cancer cells. The publication by Fanjul et al. in Cancer Research 56, 1571-1577 (1996) describes assays of several retinoid compounds, including a compound designated in the publication as SRI 11220 in combination with interferon in several carcinoma cell lines, and states that in some of the cell lines the anti-proliferative activity of the compound SRI 11220 and interferon was synergistic. The structure of this prior art compound SRI 11220 is shown below. Significantly however, the Fanjul et al. reference attributes the inhibition of breast cancer cells by selective retinoids and interferon to the potential role of the RARxcex3 receptors. In fact, the compound SRI 11220 is disclosed in this reference as an RARxcex3 agonist. 
A publication by Toma et al. in International Journal of Oncology 10: 597-607 (1997) describes synergistic effects of certain other retinoids, such as all trans retinoic acid (tRA) with xcex1 interferon (xcex1 IFN) and synergistic effect with other chemotherapeutic agents such as tamoxifen (TAM) in MCF-7 human breast cancer lines. As further background to the present invention it is noted that a publication by Kurbacher et al. in Cancer Letters 103 (1996) 183-189 describes synergistic action of vitamin C with certain chemotherapeutic anti-tumor agents in MCF-7 and MDA-MB 231 human carcinoma cell lines.
U.S. Pat. No. 5,856,490 discloses aryl or heteroarylamides of tetrahydronaphthalenes, which are generally speaking RARxcex1 specific retinoids. Among the compounds specifically described as preferred embodiments in that reference is the 2,6-difluoro-4-[3xe2x80x2-hydroxy-4xe2x80x2-bromo-5xe2x80x2,6xe2x80x2,7xe2x80x2,8xe2x80x2-tetrahydro-5xe2x80x25xe2x80x2,8xe2x80x2,8xe2x80x2-tetramethylnaphthalen-2xe2x80x2-yl)carbamoyl]benzoic acid, the structure of which is shown above. In the U.S. Pat. No. 5,856,490 reference this compound is designated compound 36.
The present invention relates to the use of RARxcex1 specific or selective retinoids in combination with other anti-tumor agents for the treatment of a malignant tumor or condition in a mammal in need of such treatment. The RARxcex1 specific or selective retinoid is generally speaking administered to the mammal in need of such treatment in a pharmaceutical composition comprising a pharmaceutically acceptable excipient and the RARxcex1 specific or selective retinoid as the active ingredient. The other anti-tumor agent of the combination therapy may be administered in the same or in a different pharmaceutical composition.
The present invention also relates to compounds of Formula 1 
where R represents H or a lower alkyl group having 1 to 6 carbons, and to pharmaceutically acceptable salts of said compounds, and to the use of compounds of Formula 1 in combination with other anti-tumor agents for the treatment of a malignant tumor or condition in a mammal in need of such treatment. Furthermore, the present invention also relates to a pharmaceutical composition for treatment of a malignant tumor or condition in a mammal in need of such treatment, where the active ingredient of the composition comprises one or more compounds of Formula 1. Such pharmaceutical composition comprising as its active ingredient one or more compounds of Formula 1 is advantageously used in combination with one or more other anti-tumor agents for the treatment of a malignant tumor or condition in a mammal in need of such treatment.